WO2007061717A2 - Procedes de separation d’amino-indanes propargyles - Google Patents
Procedes de separation d’amino-indanes propargyles Download PDFInfo
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- WO2007061717A2 WO2007061717A2 PCT/US2006/044327 US2006044327W WO2007061717A2 WO 2007061717 A2 WO2007061717 A2 WO 2007061717A2 US 2006044327 W US2006044327 W US 2006044327W WO 2007061717 A2 WO2007061717 A2 WO 2007061717A2
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- Prior art keywords
- aminoindan
- salt
- mono
- reaction mixture
- propargylated
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- FUHWUVYVLXDPDH-UHFFFAOYSA-N CCN(C)C(OC)=O Chemical compound CCN(C)C(OC)=O FUHWUVYVLXDPDH-UHFFFAOYSA-N 0.000 description 1
- 0 COC(N(*)*)=* Chemical compound COC(N(*)*)=* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Definitions
- the present invention concerns methods of isolation of secondary propargylated aminoindan derivatives from a reaction mixture.
- the secondary propargylated aminoindan rasagiline has been shown to be a selective inhibitor of MAO-B, and useful in treating Parkinson's disease and various other conditions.
- United States Patent Number 5,532,415 discloses rasagiline (R (+) -N-propargyl-1-aminoindan (R(+)PAI)), its preparation, and various pharmaceutically acceptable salts thereof.
- Another secondary propargylated aminoindan is R(+)-6-(N- methyl , N-ethyl-carbamoyloxy) -N ' -propargyl-1-aminoindan, also known as (3R) -3- (prop-2-ynylamino) -2, 3, -dihydro-lH- inden-5-yl ethylmethylcarbamate, which has been disclosed in PCT International Application Publication No. • WO98/27055 (U.S. Patent No. 6,303,650, issued October 16, 2001 to Chorev) .
- its preparation and its salts are disclosed, including the 1/2 L-tartrate salt.
- the 1/2 L-tartrate salt has been given the nonproprietary name ladostigil tartrate. Its CAS registry number is 209394-46-7.
- PCT International Application Publication No. WO98/27055 also discloses aminoindans having the formula:
- b is 1 or 2; in is 0-3; Y is 0 or S; X is halo; R 1 is hydrogen or Ci- 4 alkyl; R 2 is hydrogen, Ci_ 4 alkyl, or optionally substituted propargyl; and R 3 and R 4 are each independently, Ci-s alkyl, C ⁇ -12 aryl, C 6 -12 aralkyl, each optionally halo substituted, or hydrogen.
- ADD Attention Deficit Disorder
- ADHD Attention Deficit and Hyperactivity Disorder
- Tourett's Syndrome Alzheimer's Disease and other dementias.
- United States Patent Number 5,532,415 describes how an enantiomerically pure propargyl aminoindan can also be prepared directly from the optically active R-enantiomer of 1-aminoindan by reaction with propargyl bromide or propargyl chloride or a propargyl sulfonate ester in the presence of an organic or inorganic base, and optionally in the presence of a suitable solvent.
- Suitable organic or inorganic bases for use in such reaction include, by way of example, triethylamine, pyridine, alkali metal carbonates, and bicarbonates .
- the solvent may be chosen from, e.g., toluene, methylene chloride, and acetonitrile.
- the subject invention provides a process for isolating from a reaction mixture a salt of a mono-propargylated aminoindan having the structure
- R 1 is H, hydroxyl, alkoxy or
- R 2 and R 3 is each, independently, Ci_ a alkyl, C 6 -i2 aryl, C6-12 aralkyl, each optionally halo substituted, or hydrogen;
- reaction mixture further comprises a solvent, a primary aminoindan having the structure
- the process comprising a) adding an acid to the reaction mixture; b) crystallizing the mono-propargylated aminoindan under conditions suitable for the formation of a crystalline salt of the mono-propargylated aminoindan; and c) recovering the crystalline salt of the mono- propargylated aminoindan, wherein the process is performed without addition of an organic solvent .
- the subject invention also provides a process for isolating from a reaction mixture a diastereomeric salt of a mono-propargylated aminoindan having the structure
- Ri is H, hydroxyl, alkoxy or
- R 2 and R3 is each, independently, Ci_ a alkyl, C6-12 aryl, Ce-12 aralkyl, each optionally halo substituted, or hydrogen;
- reaction mixture further comprises a solvent, a racemic primary aminoindan having the structure wherein Ri is defined as above, and a racemic tertiary aminoindan having the structure
- said process comprising a) adding a firs't acid to the reaction mixture in an amount sufficient to form a crystalline acid addition salt of the primary aminoindan; b) removing the crystalline acid addition salt said of the primary aminoindan from the reaction mixture, thereby separating the primary aminoindan from the reaction mixture; c) adding a second acid to the reaction mixture under conditions suitable for the formation of the crystalline salt of mono-propargylated aminoindan; and i d) recovering the crystalline salt of the mono- propargylated aminoindan .
- the subject invention also provides a process for isolating from a reaction mixture a diastereomeric salt of a mono-propargylated aminoindan having the structure wherein Ri is H, hydroxyl, alkoxy or
- R 2 and R 3 is each, independently, Ci_ 8 alkyl, C 6 -i2 aryl, Ce-i2 aralkyl, each optionally halo substituted, or hydrogen;
- reaction mixture further comprises a solvent, a racemic primary aminoindan having the structure
- Rl is defined as above, and a racemic tertiary aminoindan having the structure
- said process comprising a) adding a chiral acid to the reaction mixture in an amount equivalent to the mono-propargylated aminoindan derivative • to form a crude _ g _
- the subject invention also provides a process for isolating from a reaction mixture a salt of enantiomerically pure N-propargyl-1-aminoindan or a salt of enantiomerically pure 6-(N-methyl, N-ethyl- carbamoyloxy) -N' -propargyl-1-aminoindan, wherein the reaction mixture further comprises a primary aminoindan having the structure
- a tertiary aminoindan having the structure the process comprising crystallizing the salt of enantiomerically pure N-propargyl-1-aminoindan or the salt of enantiomerically pure 6- (N-methyl, N- ethyl-carbamoyloxy) -N' -propargyl-1-aminoindan, wherein the process is performed without addition of an organic solvent .
- Figure 1 Block diagram depicting rasagiline tartrate isolation via primary aminoindan crystallization.
- Figure 2 Block diagram depicting rasagiline tartrate isolation via water recrystallization .
- Figures 3a-b Micrographs (10Ox and 5Ox magnification, respectively) of rasagiline tartrate crystals prepared according to Example 1.
- Figures 4a-b Micrographs (10Ox and 5Ox magnification, respectively) of rasagiline tartrate crystals prepared according to Example 15.
- Figures 5a-b Micrographs (15Ox and 30Ox magnification, respectively) of ladostigil tartrate crystals prepared according to Example 16.
- Figures 6a-b Micrographs (10Ox and 5Ox magnification, respectively) of rasagiline tartrate crystals prepared according to Example 18.
- Figures 7a-b Micrographs (10Ox and 5Ox magnification, respectively) of rasagiline tartrate crystals prepared according to Example 19. u ⁇ cax ⁇ Description of the Invention
- the subject invention provides a process for isolating from a reaction mixture a salt of a mono-propargylated aminoindan having the structure
- Ri is H, hydroxyl, alkoxy or
- R2 and R 3 is each, independently, Ci_ 8 alkyl, C6-12 aryl, C 6 -i2 aralkyl, each optionally halo substituted, or hydrogen;
- reaction mixture further comprises a solvent, a primary aminoindan having the structure
- R 1 is defined as above, and a tertiary aminoindan having the structure
- the process comprising a) adding an acid to the reaction mixture; b) crystallizing the mono-propargylated aminoindan under conditions suitable for the formation of a crystalline salt of the mono-propargylated aminoindan; and c) recovering the crystalline salt of the mono- propargylated aminoindan, wherein the process is performed without addition of an organic solvent.
- the wavy line used . in the structure of the mono- propargylated aminoindan represents a compound that is racemic, enantiomerically pure or enantiomerically enriched.
- a) comprises: 1) adding a first acid to the reaction mixture in an amount sufficient to form a crystalline acid addition salt of the primary aminoindan;
- step b) comprises addition of a second acid to the reaction mixture under conditions suitable for the formation of the crystalline salt of mono-propargylated aminoindan.
- the subject invention also provides a process for isolating from a reaction mixture a diastereomeric salt of a mono-propargylated aminoindan having the structure wherein R 1 is H, hydroxyl, alkoxy or
- R 2 and R 3 is each, independently, Ci- 8 alkyl, Ce-i2 aryl, C 6 -i2 aralkyl, each optionally halo substituted, or hydrogen;
- reaction mixture further comprises a solvent, a racemic primary aminoindan having the structure
- said process comprising a) adding a first acid to the reaction mixture in an amount sufficient to form a crystalline acid addition salt of the primary aminoindan; b) removing the crystalline acid addition salt said of the primary aminoindan from the reaction mixture, thereby separating the primary aminoindan from the reaction mixture; c) adding a second acid to the reaction mixture under conditions suitable for the formation of the crystalline salt of mono-propargylated aminoindan; and d) recovering the crystalline salt of the mono- propargylated aminoindan .
- the first acid is added in a quench amount to the primary aminoindan in the reaction mixture.
- the first acid is sulfuric acid or tartaric acid.
- the solvent in the reaction mixture is isopropanol .
- the crystalline acid addition salt of the primary aminoindan is removed by filtration.
- the process may further comprise a step of washing the crystalline salt of the mono-propargylated aminoindan.
- step a) comprises: 1) adding a chiral acid to the reaction mixture in an amount equivalent to the mono- propargylated aminoindan to form a crude diastereomeric salt of the mono-propargylated aminoindan; and 2) separating the crude diastereomeric salt of the mono-propargylated aminoindan from the reaction mixture.
- step b) comprises recrystallization of the crude diastereomeric salt of mono-propargylated aminoindan in water.
- the subject invention also provides a process for isolating from a reaction mixture a diastereomeric salt of a mono-propargylated aminoindan having the structure
- Ri is H, hydroxyl, alkoxy or
- R 2 and R 3 is each, independently, Ci_ 8 alkyl, C 6 -i 2 aryl, C 6 _i 2 aralkyl, each optionally halo substituted, or hydrogen;
- reaction mixture further comprises a solvent, a racemic primary aminoindan having the structure
- Rl is defined as above, and a racemic tertiary axninoindan having the structure
- said process comprising a) adding a chiral acid to the reaction mixture in an amount equivalent to the mono-propargylated aminoindan derivative to form a crude diastereomeric salt of the monopropargylated aminoindan; b) separating the crude diastereomeric salt of the mono-propargylated aminoindan from the reaction mixture; c) recrystallizing the crude diastereomeric salt of the mono-propargylated aminoindan in water to isolate crystalline diastereomeric salt of the mono-propargylated aminoindan; and d) recovering crystalline diastereomeric salt of the mono-propargylated aminoindan.
- Ri is H.
- R 2 is H or Ci-C 4 alkyl and R 3 is C 1 -C 4 alkyl . 061717 _ 18 _
- R 2 is methyl and R 3 is ethyl .
- Ri is attached to the carbon at the 6 position.
- the chiral acid is L-tartaric acid and the diastereomeric salt is the L-tartrate salt.
- the mono- propargylated aminoindan tartrate salt is 99% pure, 98% pure, 97% pure, 95% pure or 90% pure.
- the mono- ⁇ ropargylated aminoindan tartrate salt is 99% enantiomerically enriched, 98% enantiomerically enriched, 97% enantiomerically enriched, 95% enantiomerically enriched or 90% enantiomerically enriched.
- the mono- propargylated aminoindan tartrate salt is ladostigil tartrate.
- the process may further comprise converting the mono- propargylated aminoindan diastereomeric salt into a mesylate salt.
- the mono- propargylated aminoindan diastereomeric mesylate salt is rasagiline mesylate.
- me subject invention also provides a process for isolating from a reaction mixture a salt of enantiomerically pure N-propargyl-1-aminoindan or a salt of enantiomerically pure 6- (N-methyl, N-ethyl- carbamoyloxy) -N' -propargyl-1-aminoindan, wherein the reaction mixture further comprises a primary aminoindan having the structure
- R 1 is H or
- the enantiomerically pure N-pro ⁇ argyl-1-aminoindan is R(+) -N-propargyl-1- aminoindan
- the enantiomerically pure 6- (N-methyl, N-ethyl-carbamoyloxy) -N' -propargyl-1-aminoindan is R(+)- 6- (N-methyl, N-ethyl-carbamoyloxy) -N' -propargyl-1- aminoindan
- the salt of R(+)- N-propargyl-1-aminoindan is the tartrate salt and the salt of R(+) -6- (N-methyl, N-ethyl-carbamoyloxy) -N' - propargyl-1-aminoindan is the tartrate salt.
- the subject invention also provides crystalline diastereomeric salt of the mono-propargylated aminoindan prepared by the processes described herein having an aspect ratio of less than 15, less than 12 or less than 10, and a pharmaceutical composition comprising the crystalline diastereomeric salt.
- the subject invention also provides crystalline rasagiline tartrate salt having an aspect ratio of less than 15, less than 12 or less than 10, and a pharmaceutical composition comprising the crystalline rasagiline tartrate salt.
- Ri is defined as H, hydroxyl , alkoxy or
- Y may be 0 or S
- R 2 and R 3 may each be, independently, C ⁇ s alkyl, C6-12 aryl, C6-12 aralkyl, each optionally halo substituted, or hydrogen
- X may be Cl, Br, I, PhSO 3 , MeSO 3 , or Me-PheS0 3 .
- This reaction can also be performed with an enantiomerically pure primary amine as a starting reagent, which will result in only one secondary amine enantiomer being formed.
- the reaction of aminoindan derivatives with propargylating agents is not selective- When the molar ratio of starting aminoindan derivative to propargylating agent is approximately 1:1, the reaction mixture results in a racemic mixture of the "primary” aminoindan derivatives, "secondary” or propargyl aminoindan derivatives, and "tertiary” or di- propargylated aminoindan derivatives . Adding an excess 061717 _ 22 _
- a propargylating reagent results in a complete conversion of the starting aminoindan derivative but it increases the yield of the di-propargylated aminoindan derivative.
- the starting material could be recovered from the reaction mixture, but an excess of the di- propargylated aminoindan derivative should be avoided. Therefore the preferred molar ratio of propargylating reagent to starting aminoindan is 1:1.
- the reaction of a racemic 1-aminoindan derivative with a propargyl chloride, bromide, or a propargyl sulfonate ester results in a mixture of unreacted primary amine derivative, a racemic mixture of the desired secondary amine derivative and the tertiary amine N, N-bispropargylamino product.
- the desired secondary amine e.g., R (+) -N-propargyl-1-aminoindan
- R (+) -N-propargyl-1-aminoindan can be separated from this mixture by a conventional separation method including, by way of example, chromatography, distillation and selective extraction. After separation of the desired secondary propargylated amine derivative, salt formation and/or enantiomeric isolation can be performed.
- the conventional separation methods have their respective shortcomings .
- Another example of a resolution method is the formation of diastereomeric salts with a chiral acid such as tartaric, malic, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine, followed by recrystallization to isolate the diastereomeric salt of the desired R enantiomer.
- a direct isolation process was attempted for the aminoindan derivatives discussed herein.
- Direct isolation processes are processes designed to crystallize or precipitate the desired product directly from the reaction mixture so as 061717 _ ⁇ _
- the approach undertaken for the isolation of aminoindan derivatives discussed herein involved the use of chiral acids to directly precipitate the desired product.
- the relative amounts of reaction products and starting materials in the aminoindan reaction mixture can be determined by readily available methods such as high pressure liquid chromatography. Once the relative amounts of reaction products and starting materials in the reaction mixture are known, the amounts of an acid needed to initiate crystallization can be calculated.
- Chiral acids contain a carbon atom that is surrounded by four different groups, allowing for isomers that are non-superimposable mirror-images (leading to optical isomerism) .
- Examples of such chiral acids include: tartaric acid, malic acid, mandelic acid or N-acetyl derivatives of amino acids, such as N-acetyl leucine.
- Other examples of chiral acids known in the art are disclosed in J. Jacques, A Collet and S. Wilen, "Enantiomers, Racemates and Resolutions," Wiley, New York (1981) .
- Chiral acids are acids which when combined with a racemic mixture of an aminoindan derivative free base will form diastereomeric salts with primarily one of the enantiomers.
- Diastereomeric salt refers to salt with two chiral centers, wmch is formed by mixing a racemate with a chirally- pure compound.
- the "aminoindan crystallization method” is represented in Figure 1 and involves the following steps : 61717 - 25 - adding a first acid to the reaction mixture, in an equivalent amount to form a primary optionally- substituted aminoindan acid addition salt, removing the optionally substituted primary aminoindan acid addition salt from the reaction mixture, adding L-tartaric acid to the reaction mixture to form a mono-propargylated aminoindan tartrate salt, and - removing the mono-propargylated aminoindan tartrate salt from the reaction mixture.
- aminoindan crystallization method One of the advantages of the "aminoindan crystallization method" is that primary aminoindan derivatives of high purity are isolated and may be reused in the propargylation reaction. Another advantage is that this method requires less organic solvent than the prior art extraction method, and does not require disposal of large amounts of acidic solvents .
- Another advantage of recrystallization of rasagiline tartrate in water is the production of large, rod-shaped crystals, as opposed to smaller, needle-shaped crystals.
- the needle-shaped crystals are characterized by aggregation and lower density which reduces their workability.
- Rod-shaped crystals could provide better processability of the product including flowability of a slurry, solid filterability and improved cake wash.
- needle-shaped crystals have been shown to cause processability problems when making pharmaceutical compositions using conventional tableting devices.
- needle-shaped crystals are often difficult to coat, thereby precluding their use in controlled release pharmaceutical dosage forms. See, e.g. Rouhi, Chemical & Engineering News, Washington, February 24, 2003.
- Rod- shaped crystals do not suffer from such limitations.
- the water recrystallization method eliminated aminoindan impurity and unexpectedly provided additional enantiomeric purity.
- Pure refers to the absence of extraneous elements of any kind, to the extent detectable by available techniques .
- Enantiomerically pure refers to a state in which one enantiomer is absent, to the extent detectable by available techniques .
- the stirrer was stopped and the reaction mixture was allowed to settle. After phase separation, the lower aqueous phase was discarded.
- the upper organic phase was mixed with 300ml of water and was stirred. The resulting mixture was acidified with 66% sulfuric acid to a pH of 2.2 and stirring was stopped. The mixture was settled for 1/2 hour and the lower phase (acidic aqueous layer) was separated. The upper organic phase was discarded.
- the aqueous phase was mixed with 250ml of toluene while stirring and was basified to a pH of 6.3 with a 25% solution of NaOH. After the pH was adjusted to 6.3, the stirrer was stopped and the mixture was allowed to settle. The lower aqueous phase and the upper toluenic phase were separated. The aqueous phase was reintroduced into the reactor, mixed with an additional 200 ml of toluene. The reactor was stirred and the pH was adjusted to 7.0 with a 25% solution of NaOH. After pH adjustment, the stirrer was stopped and the mixture was allowed to settle. The lower aqueous phase was separated and discarded. The organic toluene phase was combined with the organic toluene phase from the previous extraction /061717 - 29 -
- PAI base was dissolved in 225ml isopropanol, stirred, heated to reflux and the solution of L-tartaric acid was added to the PAI solution at ref] ⁇ IX conditions .
- the addition resulted in crystallization of solid rasagiline tartrate salt.
- the suspension was cooled to room temperature, filtered and the solid product was washed on a filter with two portions of isopropanol.
- Solid morphology Aggregated small (100-300 micron) needle-shaped crystals.
- the lower aqueous phase was discarded and the upper organic phase was mixed with 250 ml of water and was stirred.
- the mixture was acidified with 66% Sulfuric Acid to a pH of 2.0. After the acidification, the stirrer was stopped, and the mixture was allowed to settle. After phase separation, the upper organic layer was discarded and the lower aqueous phase was reintroduced into the reactor.
- the acidic aqueous phase was mixed with 200ml toluene, stirred, and basified with 25% NaOH to a pH of 5.2.
- the mixture was stirred at 45 0 C, the stirrer was stopped, and the mixture was allowed to settle.
- the upper organic phase and the lower aqueous phase were separated and the aqueous phase was reintroduced into the reactor.
- Examples 1 and 2 show that extraction can be used to isolate pure (R)-PAI and (R)-CPAI tartrate salts.
- these processes require many steps and require much acidified organic solvent which is difficult to dispose of.
- Example 3 Rasagiline tartrate isolation by direct precipitation of rasagiline tartrate.
- the reactor with isopropanolic solution was heated to reflux while stirring, and the solution of L-tartaric acid was added dropwise at reflux. A solid product was precipitated during the addition of acid.
- the resulting suspension was cooled to 25 0 C, and the solid product was filtered and washed with isopropanol. The wet solid was dried under vacuum. The dry solid product (28.7g of white crystalline powder) was sampled and analyzed.
- Example 4 Rasagiline tartrate isolation by direct precipitation of rasagiline tartrate.
- the resulting brown oil (56.5g) was dissolved in 120ml of isopropanol while being stirred stirring in reactor.
- An L-tartaric acid solution was prepared by dissolving 12.6g of L-tartaric acid in 125ml isopropanol and heating .
- the solution in the reactor was heated to reflux while being stirred and then the L-tartaric acid solution was introduced to the reactor dropwise under reflux conditions .
- Example 5 Rasagiline Tartrate isolation by direct prolonged precipitation of rasagiline tartrate (slow crystallization) .
- the solution in the reactor was heated to reflux while stirring and the solution of tartaric acid was introduced to, the reactor dropwise under reflux conditions .
- Solid product was not precipitated during the addition.
- the resulting mixture was cooled and seeded with rasagiline tartrate at 73 0 C.
- the seeding material was not dissolved and at 64 0 C crystallization of the batch was observed.
- the batch was cooled to 25 0 C over 12 hours and stirred at this temperature for 6 hours.
- the solid product was filtered and washed with isopropanol .
- the wet solid was dried under vacuum. 20,6g of dry solid product in the form of white crystalline powder was sampled and analyzed.
- Examples 3, 4 and 5 show that it is difficult to directly separate pure mono-propargylated aminoindan derivative from the reaction mixture .
- the crude salts produced upon the addition of L-tartaric acid to the reaction mixture are contaminated by primary aminoindan as well as by S-enantiomer.
- Examples 6-11 relate to rasagiline and Examples 10-11 relate to ladostigil.
- Example 6 Rasagiline tartrate separation by aminoindan tartrate precipitation and separation.
- An acidic solution was prepared by dissolving 4.12g of L-tartaric acid in 6.4ml water.
- the solution in the reactor was heated to reflux at stirring and the solution of tartaric acid was introduced to the reactor dropwise under reflux conditions .
- the filtrates were introduced into a reactor and stirred.
- An acidic solution was prepared by dissolving 8.24g of L-tartaric acid was dissolved in 12.9ml water.
- the solution in the reactor was heated to reflux while stirring and the solution of tartaric acid was introduced to the reactor dropwise under reflux conditions .
- Solid product was precipitated during the addition.
- the resulting suspension was cooled to 25 0 C and the solid product was filtered and washed with isopropanol .
- the wet solid was dried under vacuum. 23.3g of dry solid product in the form of white crystalline powder were sampled and analyzed.
- Example 7 Rasagiline tartrate preparation by aminoindan sulfate precipitation and separation.
- Racemic aminoindan sulfate precipitation 1-aminoindan (45g) , toluene (135ml), water (85ml) and NaOH (6Og of 25% solution) were introduced into a reactor, stirred, and PBS (67.5g) was added at ambient temperature. The reaction mass was heated to 45 0 C and held at this temperature for 4 hours.
- Sulfuric acid were introduced to the reactor dropwise at ambient temperature.
- Example 8 Pure 1-aminoindan tartrate control preparation.
- Ig of pure 1-aminoindan was dissolved in 25 ml isopropanol in a glass flask equipped with a magnetic stirrer and a thermometer. The solution was heated to
- the resulting suspension was cooled to 25 0 C and filtered.
- Example 9 Pure 1-aminoindan sulfate control preparation .
- Examples 8 and 9 provided control compounds for comparison of purity of aminoindan salts.
- the primary aminoindan salts formed by crystallization from the reaction mixture in examples 6 and 7 were of high purity. These salts could be easily re-used in propargyl aminoindan synthesis, thereby significantly reducing the amount of wasted starting material.
- the (R)-PAI tartrate salts formed by crystallization from the reaction mixture in examples 6 and 7 were of high purity and high enantiomeric purity. This shows that this 1 method of isolation of (R)-PAI tartrate salts is effective. In addition, it uses fewer steps, uses less solvent, and generates less environmentally-unfriendly waste than the extraction method.
- the reaction mass was stirred at 45-46 0 C over 5 hours.
- the stirrer was stopped, and the mixture was allowed to settle.
- the lower aqueous layer was discarded.
- the upper organic layer was washed with 70ml water and was evaporated under vacuum in a rotating evaporator.
- the residue which resulted from evaporation was dissolved in 70ml isopropanol and the solvent was evaporated under the same conditions .
- the resulting brown oil (28g) was dissolved in 207ml isopropanol by stirring in a reactor. 1.63g of 66% Sulfuric Acid (1.08g anhydrous) was introduced into the reactor dropwise at ambient temperature. The mixture was stirred over 24 hours at 15-25 0 C, and no solid precipitation was observed. The reactor was seeded at 25 0 C with the solid R-CAI Sulfate from example 10. Immediately after the seeding, product crystallization was observed. The resulting suspension was stirred at 25 0 C for one hour and was filtered. The solid product was washed with isopropanol on a filter and was dried under vacuum. The mother liquor filtrate and the filtrate from the washing were collected and combined. 6.Og of dry solid product in the form of white crystalline powder was sampled and analyzed.
- the filtrates were introduced into a reactor and stirred.
- the solution in the reactor was heated to reflux while stirring and 6.Og of solid L-tartaric acid were introduced into the reactor under reflux conditions.
- a solid product precipitated after the addition of acid.
- the resulting suspension was cooled to 5 0 C and the solid product was filtered and washed with isopropanol.
- the wet solid was dried under vacuum. 23.4g of dry solid product in the form of white crystalline powder was sampled and analyzed.
- Example 11 shows that pure ladostigil tartrate can be isolated from a reaction mixture by prior salt formation 061717 - 43 -
- Example 12 Rasagiline tartrate re-crystallization from water, batch A.
- the batch was stirred and heated to 60 0 C and the solids were dissolved. The solution was cooled, and at 40 0 C crystallization was observed. The batch was further cooled to 5 0 C and filtered. The solid product was washed with ice cold water on a filter and was dried under vacuum. 4.0g of dry solid product in the form of white crystalline powder was sampled and analyzed.
- Example 13 Rasagiline tartrate re-crystallization from water, batch B.
- Example 12 The filtrate and washing liquor from Example 12 were combined and evaporated at 30 0 C by passing Nitrogen through the solution while stirring. After evaporation of part of the water, precipitation of solids was observed. The suspension was cooled to 5 0 C and filtered. Solid product was washed with ice cold water on a filter and was dried under vacuum. 1.6g of dry solid product in /061717 - 44 -
- Example 15 Pure rasagiline tartrate re-crystallization from water.
- any salt form of an aminoindan derivatives of interest of the desired optical purity can be prepared using the processes disclosed herein.
- R-PAI mesylate can be prepared using the disclosed processes.
- aspects ratio is the quotient of the division of a crystal's length by its width.
- the aspect ratio of crystals can be obtained by taking micrographs of a batch of crystal . Each micrograph was then divided into five fields. The length and width of 20 representative crystals in each field was measured. The aspect ratio of each crystal was calculated by dividing the crystal length by the crystal width. The average aspect ratio for each batch was determined by dividing the sum of crystal aspect ratios by the number of crystals measured. The results are reported as an average of at least two measurements per sample.
- needle-shaped crystals are characterized by aggregation and lower density which reduces their workability. Big, rod- shaped crystals provide better processability of the product including flowability of a slurry, solid filterability and improve cake wash.
- needle-shaped crystals have been shown to cause processability problems when making pharmaceutical compositions using conventional tableting devices. For example, needle-shaped crystals are often difficult to 061717 - 48 -
- Examples 17 and 18, below were performed to recreate known processes of production of rasagiline tartrate through crystallization in a mixture of methanol and t- butylmethyl ether and through recrystallization in methanol/isopropanol (1:1) following the disclosure of U.S. Patent Number 6,630,514, issued October 7, 2003 to Youdim. The resulting crystals were then compared to the crystals produced by the processes disclosed herein.
- Example 18 Rasagiline tartrate re-crystallization from methanol/isopropanol (1:1).
- Rasagiline Tartrate 18.5g were suspended in 500ml of methanol-isopropanol mixture (1:1). The suspension was heated to boiling while stirring. An additional 280ml of the same mixture of solvents were added under reflux conditions until complete dissolution of solids was observed.
- Example 19 Rasagiline tartrate crystallization from methanol/ t-butylmethyl ether.
- a first solution of 5.Og of L-tartaric Acid in 55ml methanol was prepared and heated to reflux. Then, a solution of 5.7g of (R)-PAI in 55ml methanol was added to the first solution while heating and stirring.
- the batch was cooled to 17 0 C and filtered.
- the solid product was washed on a filter with t-butylmethyl and dried under vacuum. Dry solid product (7.6g white crystalline powder) was sampled and analyzed.
- Example 20 Measurement of aspect ratio of rasagiline tartrate produced by various methods . Slides were prepared and micrographs were taken from each batch of each example as listed below in table 1. Each micrograph was divided into five fields . The length and width of 20 representative crystals in each field were measured. The aspect ratio of each crystal was calculated by dividing the crystal length by the crystal width. The average aspect ratio for each batch was determined by dividing the sum of crystal aspect ratios by the number of crystals measured. The results are reported as an average of at least two measurements per sample.
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Abstract
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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CA2630037A CA2630037C (fr) | 2005-11-17 | 2006-11-15 | Procedes de separation d'amino-indanes propargyles |
CN200680042785.2A CN101622225B (zh) | 2005-11-17 | 2006-11-15 | 炔丙基氨基茚分离方法 |
EP06837655.7A EP1954667B1 (fr) | 2005-11-17 | 2006-11-15 | Procedes de separation d amino-indanes propargyles |
JP2008541305A JP2009521402A (ja) | 2005-11-17 | 2006-11-15 | プロパルギル化アミノインダンの分離のための方法 |
AU2006316585A AU2006316585B2 (en) | 2005-11-17 | 2006-11-15 | Methods for isolating propargylated aminoindans |
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US73816305P | 2005-11-17 | 2005-11-17 | |
US60/738,163 | 2005-11-17 |
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US (1) | US7491847B2 (fr) |
EP (1) | EP1954667B1 (fr) |
JP (2) | JP2009521402A (fr) |
CN (1) | CN101622225B (fr) |
AU (1) | AU2006316585B2 (fr) |
CA (1) | CA2630037C (fr) |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998002152A1 (fr) | 1996-07-11 | 1998-01-22 | Teva Pharmaceutical Industries Ltd. | Compositions pharmaceutiques comportant des elements s-(-)-n-propargyl-1-aminoindane |
US5786390A (en) | 1990-01-03 | 1998-07-28 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical compositions of the R-enantiomer of N-propargyl -1-aminoindan |
US6630524B1 (en) | 1999-07-12 | 2003-10-07 | Cheil Industries, Inc. | Flame retardant thermoplastic resin composition |
WO2006091656A1 (fr) | 2005-02-24 | 2006-08-31 | Teva Pharmaceutical Industries, Ltd | Cristaux de ladostigil tartrate, methodes de fabrication et compositions pharmaceutiques contenant lesdits cristaux |
Family Cites Families (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2230794A (en) * | 1939-08-16 | 1941-02-04 | Herbert C Danischewsky | Sound testing device |
US2310601A (en) * | 1940-04-18 | 1943-02-09 | Smith Engineering Works | Gyratory crusher |
US2830946A (en) * | 1953-10-15 | 1958-04-15 | Olive B Pleadwell | Electroplating apparatus |
US3253037A (en) | 1962-06-19 | 1966-05-24 | Ciba Geigy Corp | N-2-alkynyl-amino-benzocylo-alkanes |
GB1187017A (en) * | 1966-07-16 | 1970-04-08 | Aspro Nicholas Ltd | Substituted 1-Amino Indanes and Tetrahydronaphthalens |
US3513249A (en) | 1968-12-24 | 1970-05-19 | Ideal Ind | Explosion connector with improved insulating means |
US5744500A (en) | 1990-01-03 | 1998-04-28 | Teva Pharmaceutical Industries, Ltd. | Use of R-enantiomer of N-propargyl-1-aminoindan, salts, and compositions thereof |
US5844003A (en) | 1991-04-04 | 1998-12-01 | Innovations Foundation | Use of deprenyl compounds to maintain, prevent loss, or recover nerve cell function |
US5767164A (en) | 1991-04-04 | 1998-06-16 | Innovations Foundation | Use of deprenyl to rescue damaged nerve cells |
US5444095A (en) | 1991-04-04 | 1995-08-22 | University Of Toronto, Innovations Foundation | Use of deprenyl to rescue damaged nerve cells |
IL99759A (en) | 1991-10-16 | 1997-06-10 | Teva Pharma | Mono-fluorinated derivatives of n-propargyl-1-aminoindan, their preparation and pharmaceutical compositions containing them |
IL111240A (en) | 1993-10-18 | 2001-10-31 | Teva Pharma | Salts of r(+) - enantiomers of n- propargyl-1-aminoindan and pharmaceutical compositions comprising them |
DE69535315T2 (de) | 1994-01-10 | 2007-06-28 | Teva Pharmaceutical Industries Ltd. | 1-aminoindanderivate und zusammensetzungen hiervon |
IL115357A (en) | 1995-09-20 | 2000-01-31 | Teva Pharma | Stable compositions containing N-propargyl-1-aminoindan and polyhydric alcohols |
HU229507B1 (en) * | 1996-12-18 | 2014-01-28 | Technion Res & Dev Foundation | 1,2,3,4-tetrahydro-amino-naphtalenyl- and aminoindan derivatives and pharmaceutical compositions comprising them |
WO1999037293A2 (fr) | 1998-01-27 | 1999-07-29 | Thomas Thomas N | Procedes de traitement utilisant des inhibiteurs mao-a et mao-b tels que l-deprenyl |
US20040052843A1 (en) | 2001-12-24 | 2004-03-18 | Lerner E. Itzhak | Controlled release dosage forms |
AU2003219913A1 (en) * | 2002-02-27 | 2003-09-09 | Teva Pharmaceutical Industries, Ltd. | Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective mao inhibitors |
US20040010038A1 (en) | 2002-02-27 | 2004-01-15 | Eran Blaugrund | Propargylamino indan derivatives and propargylamino tetralin derivatives as brain-selective MAO inhibitors |
EP2526944B1 (fr) | 2002-11-15 | 2016-06-01 | Teva Pharmaceutical Industries Limited | Utilisation de rasagiline, avec ou sans riluzole, pour traiter la sclérose latérale amyotrophique |
US7735024B2 (en) * | 2003-10-29 | 2010-06-08 | Intel Corporation | Methods and apparatus to provide a handheld pointer-based user interface |
JP2008507586A (ja) | 2004-07-26 | 2008-03-13 | テバ ファーマシューティカル インダストリーズ リミティド | ラサグリンを含む、医薬投与剤 |
MX2007006199A (es) | 2004-11-24 | 2007-07-13 | Teva Pharma | Composiciones de desintegracion oral de rasagilina. |
MX2007010233A (es) | 2005-02-23 | 2007-11-07 | Teva Pharma | Formulaciones de rasagilina de uniformidad de contenido mejorada. |
EP1848417A1 (fr) * | 2005-02-24 | 2007-10-31 | Teva Pharmaceutical Industries Ltd | Preparations de tartrate de ladostigil |
JP5769923B2 (ja) | 2006-04-03 | 2015-08-26 | テバ ファーマシューティカル インダストリーズ リミティド | レストレスレッグス症候群の治療のためのラサギリンの使用 |
US7547806B2 (en) | 2006-12-14 | 2009-06-16 | Teva Pharmaceutical Industries, Ltd. | Tannate salt of rasagiline |
PL2101569T3 (pl) | 2006-12-14 | 2012-03-30 | Teva Pharma | Stała, krystaliczna zasada rasagaliny |
-
2006
- 2006-11-15 WO PCT/US2006/044327 patent/WO2007061717A2/fr active Application Filing
- 2006-11-15 EP EP06837655.7A patent/EP1954667B1/fr active Active
- 2006-11-15 JP JP2008541305A patent/JP2009521402A/ja active Pending
- 2006-11-15 CA CA2630037A patent/CA2630037C/fr not_active Expired - Fee Related
- 2006-11-15 US US11/600,561 patent/US7491847B2/en not_active Expired - Fee Related
- 2006-11-15 AU AU2006316585A patent/AU2006316585B2/en not_active Ceased
- 2006-11-15 CN CN200680042785.2A patent/CN101622225B/zh not_active Expired - Fee Related
-
2013
- 2013-11-11 JP JP2013233575A patent/JP2014074033A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5786390A (en) | 1990-01-03 | 1998-07-28 | Teva Pharmaceutical Industries Ltd. | Pharmaceutical compositions of the R-enantiomer of N-propargyl -1-aminoindan |
WO1998002152A1 (fr) | 1996-07-11 | 1998-01-22 | Teva Pharmaceutical Industries Ltd. | Compositions pharmaceutiques comportant des elements s-(-)-n-propargyl-1-aminoindane |
US6630524B1 (en) | 1999-07-12 | 2003-10-07 | Cheil Industries, Inc. | Flame retardant thermoplastic resin composition |
WO2006091656A1 (fr) | 2005-02-24 | 2006-08-31 | Teva Pharmaceutical Industries, Ltd | Cristaux de ladostigil tartrate, methodes de fabrication et compositions pharmaceutiques contenant lesdits cristaux |
Non-Patent Citations (1)
Title |
---|
See also references of EP1954667A2 |
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US20110105788A1 (en) * | 2008-03-28 | 2011-05-05 | Medichem, S.A. | Polymorphic Form of an Aminoindan Mesylate Derivative |
WO2009118657A2 (fr) * | 2008-03-28 | 2009-10-01 | Medichem, S.A. | Forme polymorphe d'un dérivé de mésylate d'amino-indane |
WO2009118657A3 (fr) * | 2008-03-28 | 2009-12-03 | Medichem, S.A. | Forme polymorphe d'un dérivé de mésylate d'amino-indane |
US8026397B2 (en) | 2008-05-23 | 2011-09-27 | Medichem, S.A. | Method for obtaining an aminoindan mesylate derivative |
WO2009141737A3 (fr) * | 2008-05-23 | 2010-02-04 | Medichem, S.A. | Nouveau procédé d'obtention d'un dérivé de mésylate d'aminoindane |
US7781616B2 (en) | 2008-05-23 | 2010-08-24 | Medichem, S.A. | Method for obtaining an aminoindan mesylate derivative |
US8236989B2 (en) | 2008-05-23 | 2012-08-07 | Medichem, S.A. | Method for obtaining an aminoindan mesylate derivative |
WO2009141737A2 (fr) * | 2008-05-23 | 2009-11-26 | Medichem, S.A. | Nouveau procédé d'obtention d'un dérivé de mésylate d'aminoindane |
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US8569545B2 (en) | 2008-06-02 | 2013-10-29 | Generics (Uk) Limited | Process for the preparation of enantiomerically pure amines |
JP2011525489A (ja) * | 2008-06-19 | 2011-09-22 | テバ ファーマシューティカル インダストリーズ リミティド | ラサリジン塩基の精製方法 |
EP2299992A4 (fr) * | 2008-06-19 | 2015-10-21 | Teva Pharma | Processus de préparation et de séchage de rasagiline base solide |
WO2011012140A2 (fr) | 2008-07-11 | 2011-02-03 | Synthon Bv | Polymorphes de chlorhydrate de rasagiline |
WO2010007181A2 (fr) * | 2008-07-18 | 2010-01-21 | Medichem, S.A. | Nouvelles formes de sels d’un dérivé d’aminoindane |
WO2010007181A3 (fr) * | 2008-07-18 | 2010-07-29 | Medichem, S.A. | Nouvelles formes de sels d’un dérivé d’aminoindane |
CN102149671A (zh) * | 2008-07-30 | 2011-08-10 | 基因里克斯(英国)有限公司 | 甲磺酸雷沙吉兰的多晶形式 |
WO2010013048A1 (fr) * | 2008-07-30 | 2010-02-04 | Generics [Uk] Limited | Forme polymorphe de mésilate de rasagiline |
WO2011064216A1 (fr) | 2009-11-24 | 2011-06-03 | Lek Pharmaceuticals D.D. | Nouveaux sels de la rasagiline |
EP2325159A1 (fr) | 2009-11-24 | 2011-05-25 | LEK Pharmaceuticals d.d. | Nouveaux sels de rasagiline |
EP2512453B1 (fr) | 2009-12-18 | 2016-11-09 | Ferring B.V. | Granules pour préparations pharmaceutiques, procédés et appareil pour leur production |
WO2011080589A2 (fr) | 2009-12-30 | 2011-07-07 | Actavis Group Ptc Ehf | Formes à l'état solide de sels de rasagiline |
EP2610239A1 (fr) | 2012-01-02 | 2013-07-03 | Dr. Reddy's Laboratories Ltd. | Préparation de rasagiline hémitartrate |
WO2013139387A1 (fr) | 2012-03-21 | 2013-09-26 | Synthon Bv | Compositions pharmaceutiques stabilisées contenant des sels de rasagiline |
Also Published As
Publication number | Publication date |
---|---|
EP1954667B1 (fr) | 2017-02-08 |
CA2630037C (fr) | 2015-03-31 |
AU2006316585A1 (en) | 2007-05-31 |
CN101622225B (zh) | 2015-04-15 |
JP2014074033A (ja) | 2014-04-24 |
EP1954667A2 (fr) | 2008-08-13 |
AU2006316585B2 (en) | 2012-09-20 |
US20070112217A1 (en) | 2007-05-17 |
JP2009521402A (ja) | 2009-06-04 |
US7491847B2 (en) | 2009-02-17 |
CA2630037A1 (fr) | 2007-05-31 |
CN101622225A (zh) | 2010-01-06 |
WO2007061717A3 (fr) | 2009-04-30 |
EP1954667A4 (fr) | 2011-03-23 |
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